11β-hydroxylase deficiency pathophysiology: Difference between revisions

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{{Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency}}
{{11β-hydroxylase deficiency}}
{{CMG}}; {{AE}} {{Ammu}}
 
{{CMG}}; {{AE}} {{MJ}}
==Overview==
==Overview==
Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency arises due to a defect in the [[gene]] encoding the [[enzyme]] [[steroid 11β-hydroxylase]] which mediates the final step of [[cortisol]] synthesis in the [[adrenal gland|adrenal]]. Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency is transmitted in an autosomal recessive pattern. On gross pathology, thickening of the adrenal gland and cerebriform appearance are characteristic findings of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. On microscopic histopathological analysis, diffuse cortical hyperplasia and lipid-depleted cortical cells are characteristic findings of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.
11β-Hydroxylase deficiency is a type of [[congenital adrenal hyperplasia]] resulting from a defect in [[CYP11B1]] on [[chromosome 8]]. [[CYP11B1]] [[gene]] encodes an enzyme called [[11β-hydroxylase]] in the path of [[steroid biosynthesis]]. This enzyme is located in the zona fasciculate, and converts [[Deoxycortisol|11-deoxycortisol]] to [[cortisol]] and [[11-deoxycorticosterone]]. Lack of [[11β-hydroxylase]] enzyme in different amounts results in accumulation of [[Deoxycortisol|11-deoxycortisol]], and decrease amounts of [[cortisol]] and [[11-deoxycorticosterone]]. There is an elevation of [[adrenocorticotropic hormone]] results in overproduction of [[11-deoxycorticosterone]] (DOC) by mid-childhood. [[11-deoxycorticosterone]] is a weak [[mineralocorticoid]], but because of high amounts in this disease can cause [[mineralocorticoid excess]] effects such as salt retention, volume expansion, and [[hypertension]]. Non-classic forms mostly doesn't have verifiable [[mutations]] and mild 11β-hydroxylase deficiency is currently considered a very rare cause of [[hirsutism]] and [[infertility]].
 
==Pathogenesis==
==Pathogenesis==
* 11β-Hydroxylase deficient congenital adrenal hyperplasia (11β-OH CAH) is the second most common form of [[congenital adrenal hyperplasia]] (CAH) resulting from a defect in the [[gene]] encoding the [[enzyme]] [[steroid 11β-hydroxylase]] which mediates the final step of [[cortisol]] synthesis in the [[adrenal gland|adrenal]]. 11β-Hydroxylase deficient congenital adrenal hyperplasia results in [[hypertension]] due to excessive [[mineralocorticoid]] effects. Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency also causes excessive [[androgen]] production both before and after birth and can [[virilization|virilize]] a genetically female fetus or a child of either sex.  
* [[11β-hydroxylase]] deficiency is a type of [[congenital adrenal hyperplasia]] resulting from a defect in [[CYP11B1]] on [[chromosome 8]].
===Mineralocorticoid Effects===
* [[CYP11B1]] [[gene]] encodes an enzyme called [[11β-hydroxylase]] in the path of [[steroid biosynthesis]]. This [[enzyme]] is located in the [[zona fasciculata]], and converts [[Deoxycortisol|11-deoxycortisol]] to [[cortisol]] and [[11-deoxycorticosterone]].
* [[Mineralocorticoid]] manifestations of severe congenital adrenal hyperplasia due to 11β-hydroxylase deficiency can be biphasic, changing from deficiency (salt-wasting) in early infancy to excess ([[hypertension]]) in childhood and adult life.  
* [[Cortisol]] production reduction has a negative feedback on the [[pituitary]] and increases [[corticotropin]] ([[ACTH]]) secretion. This leads to of [[Deoxycortisol|11-deoxycortisol]] [[precursors]] and then [[adrenocortical hyperplasia]].  
* Salt-wasting in early infancy does not occur in most cases of 11β-hydroxylase deficient congenital adrenal hyperplasia but can occur because of impaired production of [[aldosterone]] aggravated by the inefficiency of salt conservation in early infancy. Clinical features include poor weight gain and vomiting in the first weeks of life progress and culminate in life-threatening [[dehydration]], [[hyponatremia]], [[hyperkalemia]], and [[metabolic acidosis]] in the first month.
* With intact amount of other pathways, as a result of high [[ACTH]] concentrations, some amount of the [[Deoxycortisol|11-deoxycortisol]] precursors are metabolized to [[adrenal]] [[androgens]] and can cause [[virilization]] in a genetically female fetus or a child of either sex.
* Despite the inefficient production of aldosterone, the more characteristic mineralocorticoid effect of 11β-hydroxylase deficient congenital adrenal hyperplasia is hypertension. Progressive adrenal hyperplasia due to persistent elevation of adrenocorticotropic hormone results in extreme overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. 11-Deoxycorticosterone is a weak mineralocorticoid, but usually reaches high enough levels in this disease to cause effects of mineralocorticoid excess: salt retention, volume expansion, and [[hypertension]].<ref> Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Wikipedia (2016). https://en.wikipedia.org/wiki/Congenital_adrenal_hyperplasia_due_to_11%CE%B2-hydroxylase_deficiency Accessed on January 29, 2016</ref>
* Severity of disease depends on the amount of functional [[11β-hydroxylase]] [[enzyme]] that an individual produces. 
* [[Aldosterone]] production is decreased in this disease but there is an elevation of [[adrenocorticotropic hormone]] results in overproduction of [[11-deoxycorticosterone]] (DOC) by mid-childhood. [[11-deoxycorticosterone]] is a weak [[mineralocorticoid]], but because of high amounts in this disease can cause [[mineralocorticoid excess]] effects such as [[salt]] retention, volume expansion, and [[hypertension]].
* Non-classic forms mostly doesn't have verifiable [[mutations]] and mild [[11β-hydroxylase]] deficiency is currently considered a very rare cause of [[hirsutism]] and [[infertility]].


===Sex steroid Effects===
[[image:11- hydroxylase.gif|center|frame|800px|Adrenal steroid synthesis pathways in adrenal cortex and related enzymes <ref name="urlFile:Adrenal Steroids Pathways.svg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/wiki/File:Adrenal_Steroids_Pathways.svg|title=File:Adrenal Steroids Pathways.svg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
* Because [[Steroid 11-beta-hydroxylase|11β-hydroxylase]] activity is not necessary in the production of [[sex steroid]]s ([[androgen]]s and [[estrogen]]s), the hyperplastic adrenal cortex produces excessive amounts of [[DHEA|dehydroepiandrosterone]], [[androstenedione]], and especially [[testosterone]].
* These [[androgen]]s produce effects that are similar to those of [[21-hydroxylase deficient congenital adrenal hyperplasia]]. In the severe forms, XX (genetically female) fetuses can be markedly virilized, with [[ambiguous genitalia]] that look more male than female, though internal female organs, including [[ovary|ovaries]] and [[uterus]] develop normally.
* XY fetuses (genetic males) typically show no abnormal features related to androgen excess. A megalopenis (>22 cm/8.7in) is usually present in male patients.
* In milder mutations, androgen effects in both sexes appear in mid-childhood as early pubic hair, overgrowth, and accelerated bone age. Although "nonclassic" forms causing hirsutism and menstrual irregularities and appropriate steroid elevations have been reported, most have not had verifiable mutations and mild 11β-hydroxylase deficient congenital adrenal hyperplasia is currently considered a very rare cause of hirsutism and infertility.
* The enzyme which mediates 11β-hydroxylase activity is now known as P450c11β since it is one of the [[cytochrome P450 oxidase]] enzymes located in the inner [[mitochondrion|mitochondrial]] membrane of cells of the adrenal cortex. It is coded by a gene at 8q21-22. Like the other forms of congenital adrenal hyperplasia, a number of different defective alleles for the gene have been identified, producing varying degrees of impaired 11β-hydroxylase activity. Also like the other forms of congenital adrenal hyperplasia, 11β-OH congenital adrenal hyperplasia is inherited as an autosomal recessive disease.
* 11β-Hydroxylase mediates the final step of the [[glucocorticoid]] pathway, producing cortisol from 11-deoxycortisol. It also catalyzes the conversion of 11-deoxycorticosterone (DOC) to [[corticosterone]] in the [[mineralocorticoid]] pathway.
* Females with the classic form of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency have external genitalia that does not look clearly male or female (ambiguous genitalia). However, the internal reproductive organs develop normally. Males and females with the classic form of this condition have early development of their secondary sexual characteristics such as the growth of facial and pubic hair, deepening of the voice, the appearance of acne, and the onset of a growth spurt. The early growth spurt can prevent growth later in adolescence and lead to short stature in adulthood. In addition, approximately two-thirds of individuals with the classic form of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency have hypertension. Hypertension typically develops within the first year of life.
* Females with the non-classic form of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency have normal female genitalia. As affected females get older, they may develop excessive body hair growth (hirsutism) and irregular menstruation. Males with the non-classic form of this condition do not typically have any signs or symptoms except for short stature. Hypertension is not a feature of the non-classic form of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.<ref> Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Genetic Home Reference (2016). http://ghr.nlm.nih.gov/condition/congenital-adrenal-hyperplasia-due-to-11-beta-hydroxylase-deficiency  Accessed on January 25, 2016</ref>
[[Image:Steroidogenesis.png|thumb|center|800px|Production of DHEA from Cholesterol. ([[Cortisol]] is a [[glucocorticoid]].)]]


==Genetics==
==Genetics==
* This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
* [[11β-hydroxylase]] deficiency is an [[inherited]] [[disease]] with an [[autosomal recessive]] pattern, which means both copies of the [[gene]] in each cell have [[gene]] [[mutations]].  
* Mutations in the ''CYP11B1'' gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. The ''CYP11B1'' gene provides instructions for making an enzyme called 11-beta-hydroxylase. This enzyme is found in the adrenal glands, where it helps produce hormones called cortisol and corticosterone. Cortisol has numerous functions, such as maintaining blood sugar levels, protecting the body from stress, and suppressing inflammation. Corticosterone gets converted to the hormone aldosterone, which helps control blood pressure by maintaining proper salt and fluid levels in the body.
* Commonly, the parents of an individual with an [[autosomal recessive]] condition each carry one copy of the mutated [[gene]], but they typically do not show signs and symptoms of the condition.
* Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency is caused by a shortage (deficiency) of the 11-beta-hydroxylase enzyme. When 11-beta-hydroxylase is lacking, precursors that are used to form cortisol and corticosterone build up in the adrenal glands and are converted to androgens. The excess production of androgens leads to abnormalities of sexual development, particularly in females with congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. A buildup in the precursors used to form corticosterone increases salt retention, leading to hypertension in individuals with the classic form of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.
* Most [[CYP11B1]] [[mutations]] correspond to minimal or absent [[enzyme activity]], resulting in the classic 11β-hydroxylase deficiency phenotype.
* The amount of functional 11-beta-hydroxylase enzyme that an individual produces typically determines the extent of abnormal sexual development. Individuals with the classic form of the condition usually have ''CYP11B1'' gene mutations that result in the production of an enzyme with low levels of function or no function at all. Individuals with the non-classic form of the condition typically have ''CYP11B1'' gene mutations that lead to the production of an enzyme with moderately reduced function. The severity of the signs and symptoms of sexual development do not appear to be related to the severity of hypertension.
* A non-classic form of enzyme deficiency caused by [[CYP11B1]] mutations exists but is very rare.<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume= |issue= |pages= |year=2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref><ref name="pmid6296182">{{cite journal |vauthors=Zachmann M, Tassinari D, Prader A |title=Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients |journal=J. Clin. Endocrinol. Metab. |volume=56 |issue=2 |pages=222–9 |year=1983 |pmid=6296182 |doi=10.1210/jcem-56-2-222 |url=}}</ref><ref name="pmid28476231">{{cite journal |vauthors=Hannah-Shmouni F, Chen W, Merke DP |title=Genetics of Congenital Adrenal Hyperplasia |journal=Endocrinol. Metab. Clin. North Am. |volume=46 |issue=2 |pages=435–458 |year=2017 |pmid=28476231 |doi=10.1016/j.ecl.2017.01.008 |url=}}</ref>
[[Image:Autorecessive.png|thumb|center|600px|11β-OH CAH is autosomal recessive]]


==Associated Conditions==
==Associated Conditions==
* Hypertension
* [[Hirsutism]]
* Testicular tumor
* [[Hypertension]]
* [[Testicular tumor]]
 
==Gross Pathology==
==Gross Pathology==
* Thickening of adrenal gland<ref> Adrenocortical hyperplasia. American urological association (2016). https://www.auanet.org/education/modules/pathology/adrenal-gland/hyperplasia.cfm Accessed on January 28, 2016</ref>
[[Gross pathology]] findings in patients with 11β-hydroxylase deficiency are:<ref name="radio">Congenital adrenal hyperplasia. Dr Henry Knipe and Dr M Venkatesh . Radiopaedia.org 2015.http://radiopaedia.org/articles/congenital-adrenal-hyperplasia</ref><ref name="pmid25372578">{{cite journal |vauthors=Teixeira SR, Elias PC, Andrade MT, Melo AF, Elias Junior J |title=The role of imaging in congenital adrenal hyperplasia |journal=Arq Bras Endocrinol Metabol |volume=58 |issue=7 |pages=701–8 |year=2014 |pmid=25372578 |doi= |url=}}</ref>
* Cerebriform appearance
*Enlarged [[adrenal glands]]
*Wrinkled surface [[adrenal glands]]
*Cerebriform pattern [[adrenal glands]] ([[pathognomonic]] sign)
*Normal [[ultrasound]] appearances may also be seen
*[[Testicular]] masses may be identified representing adrenal rest tissue
[[Image:Cah.jpg|center|thumb|400px|frame|Adrenal gland, Cortex - Hyperplasia in a male rat from a chronic study. There are two adjacent foci of hyperplasia (H) in the zona fasciculata.<ref name="urlAdrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas">{{cite web |url=https://ntp.niehs.nih.gov/nnl/endocrine/adrenal/hyperpl/index.htm |title=Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas |format= |work= |accessdate=}}</ref>]]
 
==Microscopic Pathology==
==Microscopic Pathology==
* Diffuse cortical hyperplasia
In 11β-hydroxylase deficiency [[microscopic]] findings may include:
* Zona reticularis is markedly hyperplastic
* Diffuse cortical [[hyperplasia]] with smaller [[cells]]
* Lipid depleted cortical cells
* The cell [[cytoplasm]] can be vacuolated, and often more [[basophilic]]
* Rare [[mitotic]] figures may be present
* The [[hyperplastic]] cells typically lack features of cellular [[atypia]].<ref name="urlAdrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas">{{cite web |url=https://ntp.niehs.nih.gov/nnl/endocrine/adrenal/hyperpl/index.htm |title=Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas |format= |work= |accessdate=}}</ref>
 
[[Image:Cah mic.jpg|center|thumb|400px|frame|Adrenal gland, Cortex - Hyperplasia in a female rat from a chronic study. There is a hyperplastic lesion (H) in which cortical cells are increased in number but are smaller in size than adjacent normal cortical cells (NC)<ref name="urlAdrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas">{{cite web |url=https://ntp.niehs.nih.gov/nnl/endocrine/adrenal/hyperpl/index.htm |title=Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas |format= |work= |accessdate=}}</ref>]]
 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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Latest revision as of 19:36, 18 October 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Overview

11β-Hydroxylase deficiency is a type of congenital adrenal hyperplasia resulting from a defect in CYP11B1 on chromosome 8. CYP11B1 gene encodes an enzyme called 11β-hydroxylase in the path of steroid biosynthesis. This enzyme is located in the zona fasciculate, and converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone. Lack of 11β-hydroxylase enzyme in different amounts results in accumulation of 11-deoxycortisol, and decrease amounts of cortisol and 11-deoxycorticosterone. There is an elevation of adrenocorticotropic hormone results in overproduction of 11-deoxycorticosterone (DOC) by mid-childhood. 11-deoxycorticosterone is a weak mineralocorticoid, but because of high amounts in this disease can cause mineralocorticoid excess effects such as salt retention, volume expansion, and hypertension. Non-classic forms mostly doesn't have verifiable mutations and mild 11β-hydroxylase deficiency is currently considered a very rare cause of hirsutism and infertility.

Pathogenesis

Adrenal steroid synthesis pathways in adrenal cortex and related enzymes [1]

Genetics

Associated Conditions

Gross Pathology

Gross pathology findings in patients with 11β-hydroxylase deficiency are:[5][6]

Adrenal gland, Cortex - Hyperplasia in a male rat from a chronic study. There are two adjacent foci of hyperplasia (H) in the zona fasciculata.[7]

Microscopic Pathology

In 11β-hydroxylase deficiency microscopic findings may include:

Adrenal gland, Cortex - Hyperplasia in a female rat from a chronic study. There is a hyperplastic lesion (H) in which cortical cells are increased in number but are smaller in size than adjacent normal cortical cells (NC)[7]

References

  1. ↑ "File:Adrenal Steroids Pathways.svg - Wikimedia Commons".
  2. ↑ El-Maouche D, Arlt W, Merke DP (2017). "Congenital adrenal hyperplasia". Lancet. doi:10.1016/S0140-6736(17)31431-9. PMID 28576284.
  3. ↑ Zachmann M, Tassinari D, Prader A (1983). "Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients". J. Clin. Endocrinol. Metab. 56 (2): 222–9. doi:10.1210/jcem-56-2-222. PMID 6296182.
  4. ↑ Hannah-Shmouni F, Chen W, Merke DP (2017). "Genetics of Congenital Adrenal Hyperplasia". Endocrinol. Metab. Clin. North Am. 46 (2): 435–458. doi:10.1016/j.ecl.2017.01.008. PMID 28476231.
  5. ↑ Congenital adrenal hyperplasia. Dr Henry Knipe and Dr M Venkatesh . Radiopaedia.org 2015.http://radiopaedia.org/articles/congenital-adrenal-hyperplasia
  6. ↑ Teixeira SR, Elias PC, Andrade MT, Melo AF, Elias Junior J (2014). "The role of imaging in congenital adrenal hyperplasia". Arq Bras Endocrinol Metabol. 58 (7): 701–8. PMID 25372578.
  7. ↑ 7.0 7.1 7.2 "Adrenal Gland - Hyperplasia - Nonneoplastic Lesion Atlas".
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